Field of the Invention
The present invention relates to improved PAK1-blocking compounds, methods and compositions for use in treatment of cancer and other PAK1-dependent diseases/disorders. More specifically, the present invention relates to PAK1-blocking esters of acidic PAK1-blockers used for treating a variety of PAK1-dependent diseases or disorders, use of these compounds in therapeutic methods and the manufacture of therapeutics, pharmaceuticals, medicaments and/or cosmetics as well as compositions containing these compounds. However, the invention is not limited to this particular field of use.
Description of the Related Art
Chemotherapies and radiation therapy are recognized as the mainstream approaches to the treatment of cancer. Such therapies however suffer a number of drawbacks. First, they generally come with severe side effects. Drugs used in chemotherapies characteristically damage and/or destroy cells that grow rapidly, such as cancer cells. Unfortunately, these treatments also affect rapidly growing normal cells such as blood cells in the bone marrow, cells in the hair follicles, and the cells that generate sperm in the testes. Secondly, cancer cells are able to develop resistance to the chemotherapeutic agents during the course of treatment. For example, the development of cisplatin resistance is a major source of failure in the treatment of non-small cell lung cancer.
In attempts to find alternative therapies, recent studies have established that PAKs, in particular PAK1 (RAC/CDC42-activated kinase 1), are essential for both growth and metastasis of many solid tumors, but non-essential for normal cell growth (1). PAK1 is found to be essential for growth of the so-called RAS cancers such as pancreatic and colon cancers, and breast cancers, which represent more than 70% of all human cancers. PAK1 is an oncogenic/pathogenic Ser/Thr protein kinase which is known to be responsible for a variety of diseases such as cancer and benign brain tumors such as neurofibromatosis (NF) and tuberous sclerosis (TSC), and many non-tumor diseases such as AIDS, malaria, viral/bacterial infections such as influenza, Alzheimer's Disease, Huntington's, diabetes (type 2), Parkinson's disease, inflammatory diseases such as asthma and arthritis, osteoporosis, obesity, hypertension, epilepsy, depression, learning disability, schizophrenia and autism associated with fragile X syndrome (FXS) as well as hyper-pigmentation and alopecia (hair loss), have also been identified as PAK1-dependent (1). Among the major substrates of PAK1 are the oncogenic/aging kinases RAF and LIM-kinase, an oncogenic/melanogenic transcription factor called beta-catenin, and the longevity transcription factor called FOXO. RAF, LIM-kinase and beta-catenin are activated by PAK1, while FOXO is inactivated by PAK1.
There is therefore sufficient evidence to implicate PAK1 as a target for the therapy of cancer and many other PAK1-dependent diseases/disorders. Thus, PAK1-blockers bear a potentially huge market value in both pharmaceutical and cosmetic industries. There no specific compound that directly inhibits only PAK1. This is largely because the 3-D structure of ATP-binding pocket in PAK1-3 are very similar to each other. Thus, an alternative approach would be to identify a few specific “kinase cascades” that activate only PAK1.
Several synthetic PAK1-blockers have been identified, but none have been approved by Food and Drug Administration for cancer therapy. Thus, patients suffering from PAK1-dependent diseases have to rely solely on a variety of herbal therapeutics such as caffeic acid phenethyl ester (CAPE) and curcumin, the main anticancer ingredients in propolis and Indian Curry, respectively, that block PAK1 without affecting normal cell growth (1).
Interestingly, there are a variety of “acidic” herbal compounds that indicate ability to block the oncogenic/aging kinase PAK1 including caffeic acid (CA) and artepillin C (ARC) (3,5-diprenyl-4-hydroxycinnamic acid) from propolis, ursolic acid (UA), and rosmarinic acid (RA) from Rosemary leaves. The major drawback for their clinical application is poor cell permeability and bioavailability (absorption through the intestine) in vivo.
Poor bioavailability (water-insolubility) is a big problem associated with many natural PAK1-blockers. In vitro indicators suggest efficacy as PAK1 blockers, but the human body does not absorb sufficient amounts for them to be effective. Curcumin, Resveratrol, Honokiol (from Magnolia bark) all appear, but unless sufficient amounts are absorbed, they will not provide an effective therapy of PAK1 diseases/disorders.
Therefore, there is a recognized need in the art for PAK1 blockers with improved cell permeability and bioavailability for treatment of cancer or any PAK1 dependent diseases or disorders. Particularly, the previous art is deficient in this aspect. The present invention fulfills this long-standing need and desire in the art.